Diabetes mellitus afflicts over 21 million Americans, where bone or joint abnormalities are frequent co- morbidities, including periodontal disease (PD). The significance of this proposal is that data generated will fill a significant gap in the current understanding of mechanisms associated with inflammatory bone and joint destruction as co-morbidities of diabetes mellitus. The complexity of type 1 diabetes [T1D] itself and added complexity of bone and joint co-morbidities necessitates well-controlled and innovative approaches to assess the totality of potential causes. Here I present compelling data demonstrating a T1D-genotypic effect on osteoclast function in ex vivo murine models. We hypothesize that osteoclasts derived from T1D exhibit heightened sensitivity to stimulation which leads to increased bone resorption that is further augmented in vivo secondary to diabetes progression. The objective of this proposal is to characterize T1D-associated osteoclast-specific mechanisms that lead to increased bone destruction under normoglycemic, hyperglycemic, or inflammatory conditions. The current study will employ complimentary strategies to investigate osteoclast- specific bone pathologies of T1D resulting from intrinsic or extrinsic factors or originating as diabetes sequelae. Specifically, osteoclast function and their role in diabetes-associated bone pathogenesis will be studied in vivo using murine models of periodontal disease with creative experimental designs to precisely dissect mechanisms of osteoclast dysfunction in T1D. Current antiresorptive therapies directly or indirectly affect osteoclast function; however it is unclear if current antiresorptive drugs are effective in the context of intrinsic T1D-associated osteoclast defects or in the overtly diabetic microenvironment marked by hyperglycemia and inflammation. Therefore, a decisive interrogation of osteoclast-specific factors driving inflammation-induced bone loss in T1D is of immediate clinical importance. These findings will determine the necessity for and drive the development of more appropriate therapies for bone pathologies occurring in diabetics. Just as the complex mechanisms of diabetes pathogenesis (immune and metabolic) have driven diversified strategies to pharmacologically target the illness, so too must the complex mechanisms of diabetes-associated bone and joint pathologies be the impetus for new discoveries.